Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis

Time for primary review 26 days. Myocardial hypertrophy (Hyp) and heart failure (HF) are pathologic states characterized by altered intracellular Ca handling 1, 2 that can contribute to diastolic and/or systolic dysfunction and arrhythmias 1, 3. However, there is an important interplay between intracellular Na (Nai) and Ca handling, so that altered levels of Nai and Na transporters can have profound effects on both contractile function and arrhythmogenesis. Both intracellular \ (Cai) and intracellular pH (pHi) in cardiac myocytes depend strongly on Nai 1. This is because Na/Ca exchange (NCX) and Na/H exchange (NHE) are powerful transport mechanisms that use the energy stored in the transmembrane Na electrochemical gradient to extrude Ca and protons from the cell. Thus, when Nai rises it can limit the ability of NCX and NHE to extrude Ca and protons from myocytes. This could slow relaxation and recovery of pHi from acid loads (e. g. during ischemia). First let us consider whether Nai is altered in hypertrophy and HF. Numerous reports indicate that Nai is increased in hypertrophy 4–7. The magnitude of Nai elevation (4–6 mM) in hypertrophied guinea pig hearts (induced by aortic banding) was consistent, whether measured by ion-sensitive electrodes (ISE) 4 or nuclear magnetic resonance 5. Additionally, myocytes from hypertrophied rat hearts (induced by isoproterenol infusion) exhibit a ∼6 mM increase in Nai assessed by ISE 6. Dogs with hypertrophy induced by chronic AV block (cAVB) demonstrate a ∼4 mM increase in subsarcolemmal Na compared to controls 7. However, Baudet et al. 8 detected no change in intracellular Na activity in hypertrophied ferret heart using ISE. Data regarding Nai in heart failure are more limited. In an arrhythmogenic non-ischemic HF rabbit model (induced by aortic insufficiency and … * Corresponding author.